Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits.
OBJECTIVE
Anandamides have been observed to lower intraocular pressure in the rabbit eye, preceded by a period of hypertension. Amidases are thought to catabolize these compounds into their component parts, including arachidonic acid. Direct application of arachidonic acid has been observed to cause a marked rise of intraocular pressure. Thus, anandamide analogs resistant to catabolism were thought possibly devoid of this initial hypertension, and their effects on rabbit IOP investigated.


METHODS
A series of chiral alpha-substituted anandamides were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-beta-cyclodextrin solution (containing 3% polyvinyl alcohol) and administered (62.5 micrograms) unilaterally to the eye.


RESULTS
The most promising compounds caused a statistically significant reduction of IOP (vs. vehicle) in the treated eyes. Of these, the R-alpha-isopropyl compound exhibited the best activity tested. Unlike the alpha-unsubstituted analogs previously studied, hypotensive effects were not preceded by an initial elevation of IOP and indomethacin pre-treatment (12.5 mg, s.c.) did not eliminate the IOP response, as demonstrated by administered R-alpha-isopropyl anandamide.


CONCLUSIONS
Catabolism of alpha-unsubstituted anandamides may account for their observed intraocular hypertensive effects. The physiological mechanism by which alpha-substituted anandamides work apparently differs from that of the more easily metabolized alpha-unsubstituted compounds.
Pate
D W
DW
Department of Pharmaceutical Chemistry, University of Kuopio, Finland. iha@euronet.nl
Järvinen
K
K
Urtti
A
A
Jarho
P
P
Mahadevan
V
V
Järvinen
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D063388:Endocannabinoids; D005260:Female; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D053284:Polyunsaturated Alkamides; D011817:Rabbits; D011897:Random Allocation; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C111154:R-alpha-isopropyl anandamide; C078814:anandamide; D007213:Indomethacin